This project will use anatomical and neuropathological methods to assess the kinetics and life history of Abeta deposition in the Tg2576 human APP (hAPP-Sw) transgenic mouse, which develops age related cerebral amyloidosis, behavior deficits, and electrophysiologic deficits. In the first aim, we will use quantitative anatomical, immunohistochemical and in situ techniques to characterize the time course of cerebral Abeta deposition, and evaluate the consequences of hAPP and Abeta deposition. Stereological techniques are employed to assay neuronal loss, synaptic loss, alterations in mRNA expression, and gliosis. We have recently observed phosphotau positive neurites surrounding Abeta deposits; we will characterize them immunohistochemically at the light and EM level. Dr. Chapman (project 4) has found diminished long term potentiation in the hippocampus of aged mice; we will examine glutamate receptors using quantitative immunohistochemical, in situ, and ligand binding assays. The second aim takes advantage of our observation that Abeta deposits occur specifically in the outer molecular layer of the dentate gyrus, in a region overlapping with the perforant pathway terminal zone. We will lesion the perforant pathway in young mice to test the hypothesis that Abeta in the deposits come from axonal terminals of hAPP expressing neurons. We will also lesion the perforant pathway that plaques have already formed to test the hypothesis that diminishing the among of Abeta synthesized (in the terminal zone) may uncover clearance mechanisms. Lesions of the perforant pathway are known to cause retrograde degeneration of layer II of entorhinal cortex, the cells of origin of the projection. We will examine the influence of the hAPP695Sw and hAPP695 transgenes and of Abeta deposits on the degree of degeneration. The third aim uses genetic manipulations to test hypotheses about Abeta production, deposition and clearance. We will use crosses of Tg2576 with knockout or over-expressing lines to evaluate the roles of apolipoprotein E, presenilins, a putative Abeta receptor (macrophage scavenger receptor) on the deposition of Abeta. We will also study, in collaboration with projects 1 and 2, the influence of strain background, and the impact of inducible or repressible hAPP transgenes on Abeta deposition and neuronal and synaptic loss. In sum, this project will test specific hypotheses about Abeta deposition and its consequences, and provide histopathological correlates for each of the other projects in the PPG.